Inhibitor Binding and Active Site Electrostatics in SARS-CoV-2 Main Protease
July 1, 2021
The image shows the SARS-CoV-2 main protease bound to the hepatitis-C clinical drug telaprevir (gold ). The colored surfaces around amino acid residues depict their electric charges determined with neutron crystallography – red for positive, blue for negative and gray for neutral charges.
Scientific Achievement
Drug binding of the hepatitis-C clinical inhibitor telaprevir complexed with the main protease of SARS-CoV-2 is shown to modulate the protonation states of the ionizable amino acid residues.
Significance and Impact
Knowing that the inhibitor binding modulates protonation states in the enzyme active site is critical information that assists structure-based and computational drug design.
Research Details
- This study focused on main protease (3CL Mpro) enzyme from SARS-CoV-2 in complex with the hepatitis-C clinical drug telaprevir.
- Neutron structure of the complex was determined at room-temperature, directly visualizing protonation states in the enzyme active site cavity.
“Direct observation of protonation state modulation in SARS-CoV-2 main protease upon inhibitor binding with neutron crystallography,”
Daniel W. Kneller, Gwyndalyn Phillips, Kevin L. Weiss, Qiang Zhang, Leighton Coates, and Andrii Kovalevski,
Journal of Medicinal Chemistry 64 (8), 4991-5000, (2021).
DOI: 10.1021/acs.jmedchem.1c00058
